Dr. Doug Linder

EDUCATION

Cross-Bridged Transition Metal Complexes of Cyclens: Structural Influences 

Dr. Douglas Linder (Mentor)

Abstract

Belonging to the family of G protein-coupled receptors (GPCRs), chemokine receptors are involved in a wide variety of diseases, including cancer and HIV/AIDS, as well as inflammatory disorders such as rheumatoid arthritis and inflammatory bowel disease. Their endogenous ligands, called chemokines, are small, soluble, proteins which bind to their cognate receptor and thereby elicits a cellular response. The chemokine receptor CXCR4 has been shown to be overexpressed in over 23 different human cancers including lung, ovarian, prostate and colorectal, and research has indicated that cancer progression can be efficiently mediated by small molecule chemokine receptor antagonists. Interestingly, tetraazamacrocycles have shown a remarkable high affinity for the CXCR4 receptor, with the high binding affinity achieved via multiple H-bonds and electrostatic interactions with amino acid residues on the accessible extracellular surface of the CXCR4 receptor. This work aims to investigate a series of first-row transition metal containing tetraazamacrocycle ligands, as potential chemokine receptor antagonists, detailing their structural and thermodynamic properties. The systems under investigation are based on the 1,4,7, 10- tetraazamacrocycle (cyclen) incorporating a short bridge interconnecting nonadjacent nitrogen atoms, called a cross-bridge. The cross-bridged cyclens add a topological constrained to the ligand, and in general lead to more stable metal complexes and more reactive systems. To help advance the understanding and design of these systems we will undertake a systematic theoretical investigation of the well-known di-methylene cross-bridged cyclens, and their less known trimethylene and mono-methylene cross-bridged cousins, and their first-row transition metal complexes. The following research goals are proposed: 1. Characterization of ground-state and low-energy isomers of mono-, di-, and tri-methylene cross-bridged cyclens using density functional theory (DFT) and second-order perturbation theory (MP2) electronic structure methods. 2. Characterization of Cu, and Zn complexes of the cross-bridged cyclens using DFT and MP2 methods, and 3. Determination of adsorption energies, bond dissociation energies, and structural characterization of H20, CH3Coo-, CH3COOH, and NH3 bound to the transition metal complexes of the cross-bridged cyclens, using DFT and MP2 methods. Results from the calculations should expand the knowledge of these types of antagonists and could be used to further the design of topologically constrained drugs.

CONTACT INFORMATION

Email: doug.linder@swosu.edu Office Number: CPP 205-D
Phone Number: 580-774-7179

TEACHING: BASIC COURSES

SCI 1503 Concepts of Physical Science
SCI 1501 Concepts of Physical Science Lab
CHEM 1203 Gen Chem I
CHEM 1252 Gen Chem I Lab
CHEM 1303 Gen Chem II
CHEM 1352 Gen Chem II Lab

TEACHING: PHYSICAL AND POLYMER CHEMISTRY

CHEM 4223/L Polymer Chemistry/Lab
CHEM 3343 Physical Chemistry I (no lab)
CHEM 4455/L Physical Chemistry II/Lab

OTHER ACTIVITIES

Upward Bound Instructor

RECENT PUBLICATIONS

Douglas P. Linder, Brett E. Baker, and Kenton R. Rodgers “[(H2O)Zn(Imidazole)n] 2+: the vital roles of coordination number and geometry in Zn–OH2 acidity and catalytic hydrolysis ” Physical Chemistry Chemical Physics, 2018, 20, 24979-24991. DOI: 10.1039/C8CP03121E.  

Randall D. Maples, Amy N. Cain, Benjamin P. Burke, Jon D. Silversides, Ryan E. Mewis, Thomas D’huys, Dominique Schols, Douglas P. Linder, Stephen J. Archibald, and Timothy J. Hubin “Aspartate-Based CXCR4 Chemokine Receptor Binding of Cross-Bridged Tetraazamacrocyclic Copper(II) and Zinc(II) Complexes” Chemistry – a European Journal 2016, 22, 12916-12930. DOI: 10.1002/chem.201601468.

Douglas P. Linder and Kenton R. Rodgers. “Methanethiol Binding Strengths and Deprotonation Energies in Zn(II)–Imidazole Complexes from M05-2X and MP2 Theories: Coordination Number and Geometry Influences Relevant to Zinc Enzymes” The Journal of Physical Chemistry B 2015 119(37), 12182-12192. DOI: 10.1021/acs.jpcb.5b07115.

Douglas P. Linder, Nathan J. Silvernail, Alexander Barabanschikov, Jiyong Zhao, E. Ercan Alp, Wolfgang Sturhahn, J. Timothy Sage, W. Robert Scheidt, and Kenton R. Rodgers “The Diagnostic Vibrational Signature of Pentacoordination in Heme Carbonyls” Journal of the American Chemical Society 2014 136 (28), 9818-9821.

Minmin Hu, Douglas P. Linder, Marco Buongiorno Nardelli, and Alberto Striolo “Hydrogen Adsorption on Platinum–Gold Bimetallic Nanoparticles: A Density Functional Theory Study” The Journal of Physical Chemistry C 2013 117 (29), 15050-15060.

Douglas P. Linder and Kenton R. Rodgers “Computational Modeling of Factors that Modulate the Unique FeNO Bonding in {FeNO}6 Heme-Thiolate Complexes” Journal of Biological Inorganic Chemistry 2007, 12, 721-731.